Infertility is a major health care concern affecting millions of couples worldwide, including approximately five million in the United States (5). Diagnosis and treatment of infertility are costly. About one million couples have no discernable cause for their infertility (7). Reproductive life table analysis indicates that the majority of reproductive failures occur immediately after fertilization during the preimplantation period (8).
It is important to be able to identify infertile individuals experiencing recurrent post fertilization failures. Identification of such individuals would allow more focused investigations for specific treatment of recurrent post fertilization failure. Exclusion of these individuals from treatment programs designed to enhance fertilization rather than implantation would decrease the cost of infertility therapy by eliminating inefficient treatments.
After fertilization the developing human pre-embryo takes approximately six days to traverse the oviduct, enter the uterine cavity and implant in the maternal endometrium. Implantation of the embryo, rather than fertilization, is the rate limiting process in human reproduction differentiating fertile from nonfertile cycles. Yet in the human female the events occurring between ovulation and implantation in vivo are clinically silent. A marker for fertilization before implantation was sought.
Two factors have been reported as markers of fertilization in women--embryo derived platelet activating factor (EPAF) (9-12) and early pregnancy factor (EPF) (1,2,13-17). PAF (platelet activating factor) is a potent phospholipid mediator which is produced by many cell types and has recently been implicated in numerous reproductive processes (18). EPAF production has been documented in murine, ovine and human preembryos (9,19,20). In human in vitro fertilization (IVF) embryos, increased PAF production has been related to a higher probability of clinical pregnancy (10). EPAF appears to be identical to PAF, and therefore cannot be used as a marker of fertilization in vivo since maternal serum concentrations of PAF are higher than that contributed by the embryo.
Early pregnancy factor (EPF) was first described as a pregnancy associated factor in 1976 (3). Since that time, EPF has been detected in sera from women within 24-48 hours of fertilization (1,2,13-17,21,22) or within three days of embryo transfer (14). Assays for EPF have subsequently been applied to a number of clinical situations in the woman including detection of early pregnancy failure following fertilization in normal women (1,2,13-17,21), in women with an intrauterine device (12) and in women undergoing embryo transfer (14). Even so, the measurement of EPF has not been applied to the care of patients.
Lack of clinical application of EPF into reproductive medicine can be attributed to the assay used to detect EPF. EPF has been detected by a bioassay using sheep red blood cells known as the rosette inhibition assay (RIT) (3). The RIT is complex and technically difficult to perform. Results from the RIT are semiquantitative, variable and not always reproducible (23,24). Some authors have completely failed to reproduce the phenomenon (25,26).